Effect of protein nitration on peri-gingivitis and inflammatory regulation mechanism involving nitration and de-nitration.

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In order to clarify the involvement of protein nitration in inflammation, we stimulated cultured cell lines from macrophages (RAW267) by lipopolysaccharide, tumor necrosis factor and peroxynitrite and found that peroxisome proliferator-activated receptor γ(PPARγ), one of steroid hormone receptor superfamily is strongly nitrated. Moreover, the nitrated receptors fail to move into nucleus as a transcription factor in the ligand-dependent mechanism. In addition, this receptor is nitrated in various tissues of animal models during inflammatory condition such as adjuvant-induced arthritis and ischemia-reperfusion induced intestinitis, and even in human liver from hepatitis.On the other hand, nitrated proteins during inflammation are related to cell death (apoptosis). We found that vanadate inhibits peroxynitrite-induced cell death of SH-SY5Y, that the treatment of neural stem cells with diclofenac, one of anti-inflammatory agents, results in apoptosis by inhibition of cell growth and differentiation, and that caspase-3, which works at the final stage of apoptosis, is regulated by newly found calcium binding proteins. These data indicate the existence of interaction between phosphorylation and nitration systems.We also searched the mechanism to restore the impaired function of protein by de-nitration and revealed that there is an presumably enzymatic disappearance of nitrated proteins, although it may be one of peptidases which catalyze the specific sequence of nitrated amino acids.Therefore, although we could not obtain human samples of gingivitis due to the restriction, the nitration is clarified to be involved in the regulatory system during inflammation and may be a possible target of drugs to regulate inflammation.